Alzheimer's disease ("AD") is an immutably progressing dementing disorder. It's major pathologic hallmark is the development of cytoskeletal changes in a few susceptible neuronal cells. These changes do not occur inevitably with advancing age, but once the disease has begun, spontaneous recovery or remissions are not observed.
The initial cortical changes, described further below, develop in poorly myelinated transentorhinal region of the medial temporal lobe. The destructive process then follows a predictable pattern as it extends into other cortical areas. Location of the tangle-bearing neurons and the severity of the changes allow the distinction of six stages in disease progression from stages I-II which are clinically silent to stages V-VI which mark fully developed AD. A relatively small number of patients display particularly early changes, indicating that advanced age is not a prerequisite for the evolution of the lesions. Accordingly AD is thus an age-related but not an age-dependent disease.
There are a number of current theories as to the cause and mechanism of AD progression, many associated with genetic defects. A very small percentage of AD patients have a defect on chromosome 21 relating to the gene for the production of amyloid precursor protein ("APP"). APP is a large protein involved in cell growth and repair, which, when cleaved into the small indigestible protein beta-amyloid ("B-A"), can accumulate in plaques within the brain.
Further interesting studies have focused on the relationship between late-onset familial AD and a polymorphic gene on chromosome 19 encoding for apolipoprotein-E ("apo-E"), a 34,000 molecular weight protein involved in movement of cholesterol and other lipids in and out of cells throughout the body. The role of apo-E in lipid transport and metabolism is critical and is discussed further below. The neurobiological role of apo-E has been borne from a number of observations over the years. Firstly, apo-E mRNA is abundant in the brain, where it is synthesized and secreted primarily by astrocytes (Elshourbagy et al. 1985). Secondly, apo-E containing lipoproteins are found in the cerebrospinal fluid and appear to play a major role in lipid transport in the central nervous system (Pitas et al. 1987). Thirdly, apo-E plus a source of cholesterol promotes marked neurite extension in dorsal root ganglion cells in culture (Handelmann et al. 1992). Fourthly, apo-E levels dramatically increase after peripheral nerve injury (Muller et al. 1985). Accordingly, apo-E appears to participate both in the scavenging of lipids generated after axon degeneration and in the redistribution of these lipids to sprouting neurites for axon regeneration and later to Schwann cells for remyelination of the new axons (Boyles et al. 1989).
The implication of a role for apo-E, which exists in three different isoforms encoded by three separate allelles (E-2, E-3, E-4) that are inherited in a co-dominant fashion at a single genetic locus, in the pathogenesis of AD specifically stems from the association of apo-E with the two characteristic neuropathologic lesions of AD-extracellular neuritic plaques (representing deposits of B-A) and intracellular neurofibrillary tangles (representing filaments of a microtubule-associated protein called tau). For a review, please refer to Weisgraber et al. 1994).
In particular, there has been found a genetic association between the apo-E4 isoform and AD. E4 homozygous individuals display a greater risk of developing AD than E4 heterozygotes, who in turn, display a greater risk than individuals with no E4 allelle. Although the precise mechanism by which this correlation exists remains elusive, researchers have provided some possible answers. It may involve a biological effect of the protein produced by this allelle, analogous to manner by which the decrease in the avidity of the binding of apo-E2 to the LDL receptor results in an increase in plasma cholesterol levels in E2 homozygotes. Strittmatter et al (1993) demonstrated that apo-E4 binds more effectively to the B-A peptide leading to the enhanced formation of senile plaques as compared to other two isoforms and have thereby proposed that it is not the presence of apo-E4, but the lack of the other apo-E isoforms that results in the increased predisposition to AD (Strittmatter et al. 1994a),
Similarly, with respect to the isoform-specific interaction of apo-E with tau protein, whose phosphorylated forms are the major constituent of neurofibrillary tangles, apo-E3 but not E4 has been shown to bind with tau with high avidity (Strittmatter et al. 1994a). This differential effect has led to the hypothesis that the apo-E3 normally allows tau protein to stabilize microtubules and that its decrease or absence in patients with one or two apo-E4 allelles leads to a dissociation of tau from microtubules and its enhanced phosphorylation and polymerization into the pathological paired helical filaments (Strittmatter et al. 1994b).
Despite the enormous research in the area of AD progression, treatments are scarce and methods of prevention and/or delaying the onset of this debilitating illness are virtually non-existent.
It is an object of the present invention to obviate or mitigate the above disadvantages.